Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune dysregulation resulting in the production of anti-nuclear antibodies, the generation circulating immune complexes, and the activation of the complement system. SLE leads to inflammation of various parts of the body, especially the skin, joints, blood, kidneys, lungs heart and nervous system. SLE affects approximately 1 in every 500 Americans, and strikes women 10-15 times more frequently than men. It is more common among Asians, and in China, SLE may be even more common than rheumatoid arthritis.
Although there is evidence of genetic etiology, linkage analysis suggests that there are no `major` susceptibility genes segregating in families with SLE (Shai, R., et al., Hum. Mol. Genet. 8:639-644 (1999)). Nevertheless, a number of studies have demonstrated an association between SLE and certain major histocompatibility complex (MHC) antigens (Fielder, A. H. et al., Br. Med J. (Clin. Res. Ed.)286(6363):425-8 (1983); Christiansen, F. T. et al., Aust. NZ J. Med. 13(5):483-8 (1983); Reveille, J. D. et al., Immunogenetics 21(4):299-311 (1985); Howard, P. F. et al., Am. J. Med. 81(2):187-193 (1986); Kemp, M. E. et al., Arthritis Rheum. 30(9):1015-1022 (1987)). Within the MHC region, found on the short arm of chromosome 6, are the genes for the fourth component of the complement system: C4A and C4B. These genes are highly homologous, with only an 8 nucleotide difference in exon 26. This difference leads to six amino acid changes which allow resolution on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) (Belt, K. T., et al., Cell 36(4):907-914 (1984)).
HLA-DR3 and a C4A null allele are frequently co-inherited as the extended haplotype B8,BfS:C2C,C4AQ0,C4B1;DR3. This is the most common extended haplotype in white SLE patients (Kemp, M. E. et al., Arthritis and Rheumatism 30:1015-22 (1987)). Several C4AQ0-containing haplotypes have a DNA deletion of approximately 30 kB, extending from the 5' end of the C4A gene to the same position in the C4B gene. This deletion has been classically identified using Southern blotting, and has been found to be a genetic marker for SLE (Kemp, M. E. et al., Arthritis and Rheumatism 30:1015-22 (1987)). Southern blotting, however, is a time consuming and labor intensive process.